sábado, 30 de abril de 2011

The White House on Tuesday unveiled a multi-agency plan aimed at reducing the “epidemic” of prescription drug abuse in the U.S.—including an FDA-backed education program that zeros-in on reducing the misuse and misprescribing of opioids.

Gil Kerlikowske, director of the White House Office of National Drug Control Policy, says the plan—a collaborative effort involving agencies of the departments of Justice, Health and Human Services, Veterans Affairs, Defense, and others—provides a national framework for reducing prescription drug abuse and the diversion of prescription drugs for recreational use.

In concert with the White House plan, the Food and Drug Administration (FDA) is announcing a new risk reduction program—called a Risk Evaluation and Mitigation Strategy—for all extended-release and long-acting opioid medications.

Opioids are synthetic versions of opium that are used to treat moderate and severe pain.

FDA experts say extended-release and long-acting opioids—including OxyContin, Avinza, Dolophine, Duragesic, and eight other brand names—are extensively misprescribed, misused, and abused, leading to overdoses, addiction, and even deaths across the United States. FDA says a 2007 survey revealed that more than half of opioid abusers got the drug from a friend or relative.

Opioids—such as morphine and oxycodone—are used to treat moderate and severe pain. Over the past few decades, drug makers have developed extended-release opioid formulas to treat people in pain over a long period.

The new REMS plan focuses primarily on: educating doctors about proper pain management, patient selection, and other requirements and improving patient awareness about how to use these drugs safely. As part of the plan, FDA wants companies to give patients education materials, including a medication guide that uses consumer friendly language to explain safe use and disposal.

FDA wants drug makers to work together to develop a single system for implementing the REMS strategies. Toward that goal, FDA is now notifying opioid makers that they must propose a REMS plan within 120 days.

Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research, says this risk management strategy is designed to improve pain management, while preserving patient access to these needed medications.

“This will be an important step toward addressing what has become a critical public health problem,” she says.

Doctor training, patient counseling, and other risk reduction measures developed by opioid makers as part of the REMS are expected to become effective by early 2012. They will be required for various brand name products known under the generic names:

FDA estimates that more than 33 million Americans age 12 and older misused extended-release and long-acting opioids during 2007—up from 29 million just five years earlier. And in 2006, nearly 50,000 emergency room visits were related to opioids.

"Opioid drugs have benefit when used properly and are a necessary component of pain management for certain patients, but we know that they pose serious risks when used improperly—with serious negative consequences for individuals, families, and communities," says FDA Commissioner Margaret A. Hamburg, M.D. “The prescriber education component of this Opioid REMS balances the need for continued access to these medications with stronger measures to reduce their risks."

Although doctor training is not mandatory under the REMS plan, other federal agencies are working to get Congress to link mandatory physician training to the already required Drug Enforcement Administration registration number that doctors must have to prescribe controlled substances.

FDA will also require the risk management plan to include a way to determine if the education programs are helping to reduce problems associated with long-acting and extended-release opioids, as well as allowing patients who need opioids to get them.

FDA has had the power to request companies to develop REMS since 2007. The plans may also include medication guides and patient package inserts.

This article appears on FDA's Consumer Updates page4, which features the latest on all FDA-regulated products.

To the Editor: The genus Alphavirus (family Togaviridae) comprises 29 viral species (1), grouped in at least 7 antigenic complexes by their serologic cross-reactivity (2). They are maintained in nature through enzootic cycles involving arthropods as vectors with subsequent amplification in small mammals or birds, and epizootic cycles between mosquitoes and large mammals such as horses or humans.

Few reports have been made of the circulation of alphaviruses in Uruguay. A serologic study conducted in 1970 found antibodies to western (WEEV) and eastern equine encephalitis viruses by using complement fixation and hemagglutination inhibition tests in serum specimens from children (3). In 1972–1973, epizootics in horses caused by WEEV were reported in Argentina and Uruguay, and WEEV was isolated from a sick horse (4).

We report a fatal case of viral encephalitis in April 2009 in Montevideo, Uruguay, in a previously healthy 14-year-old boy. Four days before he sought treatment, he had fever, asthenia, and headaches. At hospital admission (April 12, 2009), he was febrile and without neurologic signs; amoxicillin treatment was initiated. Results of a computed tomography scan of the brain were normal.

On day 1, headache, vomiting, neck stiffness, and partial left seizures on the left side developed. Also exhibited were consciousness depression (Glasgow Coma Scale 12 points), hyperreflexia, and bilateral Babinski sign. A cerebrospinal fluid (CSF) sample was negative for bacteria in cultures. An electroencephalogram showed diffuse brain suffering. The patient was brought to the intensive care unit with a clinical diagnosis of viral encephalitis. Over the next 24–36 hours, intracranial hypertension developed, and medical treatment was given (sedation, hyperventilation, mannitol, and barbiturates). Conscience depression progressed to a deeper level, and a computed tomography scan of the brain showed dilatation of the temporal ventricles and compression of the peritroncal and sylvian cisterns. During the next 48 hours, the coma level went deeper, reaching 6 on the Glasgow Scale. Another CSF specimen was taken, and PCR results were negative for herpesvirus and enterovirus. Glasgow Coma Scale level was 3 on April 15, and a decompressive craniectomy was done. Seventy-two hours after admission, the patient died.

The patient's plasma and CSF were tested for antibodies to dengue and West Nile viruses (immunoglobulins M and G) through ELISA (Focus Technologies, Cypress, CA, USA) and for St. Louis encephalitis and dengue virus by M antibody-capture–ELISA (5). RNA was extracted from plasma and CSF, followed by a generic nested reverse transcription–PCR (RT-PCR) for flaviviruses (6). Serologic and molecular test results were negative for the above-mentioned pathogens. Then we performed a generic nested RT-PCR (7), which amplifies 448 bp at first round and 195 bp (second round) of the alphavirus NSP4 gene. Also, a heminested PCR was done (products 372 bp and 303 bp); RNA from Venezuelan equine encephalitis virus Tc-83 (provided by M. Contigiani, Universidad de Córdoba) was used as positive control. The target region is informative enough to allow the precise identification of the most relevant alphaviruses by sequencing and phylogenetic analysis. Alphavirus genome amplification was achieved for the CSF specimen collected at admission to the hospital. Plasma and a second CSF specimen were PCR negative. To confirm these findings, another nested RT-PCR reaction targeting the NSP1 gene was done as described previously (8). A 208-bp amplicon, which corresponded to the expected size for WEEV, was obtained from plasma and the first CSF specimen.

Sequence analyses were conducted on the NSP4 fragments. Maximum likelihood (9) and Bayesian (10) phylogenetic analyses gave similar results. The Figure, panel A, shows that sample LCR/09-303 is part of a well-supported clade (aLRT = 0.99), which groups WEEVs. The sequence LCR/09-303 is a sister taxon to sequences GQ287641 and GQ287642, with poor support (Figure, panel B) (Appendix Table). These are reference WEEV USA strains (Imperial and Kern) obtained from Culex tarsalis mosquitoes. Our sample and the mentioned sequences are part of a well-supported clade (aLRT = 0.85), together with GQ287645, AF214040, and FJ786260. These are also USA strains; 2 were isolated from infected horses and 1 from Cx. tarsalis mosquitoes. Notably, our sequence is distantly related to GQ287646, which was isolated from Culex spp. mosquitoes in Chaco, Argentina. The nucleotide sequence of the positive control VEEV-Tc83 is correctly placed in the VEEV clade.

Clinical and laboratory findings showed that the illness described here was compatible with viral encephalitis. Using a generic RT-PCR assay on an early CSF sample, we amplified a partial sequence (NSP4 gene) of an alphavirus. Phylogenetic analyses showed that the patient's sequence grouped with sequences from WEEV, with high statistical support. A second RT-PCR assay on the NSP1 gene enabled us to obtain an amplification of 208 bp, which is consistent with the expected size for WEEV. Therefore, we concluded that the fatal disease was likely caused by WEEV. Since the 1970s, to our knowledge, the presence of WEEV (or other alphaviruses) in Uruguay has not been documented. Moreover, no recent reports have been made of genome detection of WEEV in encephalitis cases in the region.

Although the case described here may be rare, the etiology of many viral encephalitides in Uruguay remains unknown. Serologic studies in horses and studies to detect arboviruses in mosquito populations are being conducted to investigate the status of arbovirus infections in Uruguay.

Acknowledgments
We thank José C. Russi for his invaluable scientific advice during all the stages of this work and Gabriela Algorta for her help and interest in our research.

To the Editor: Artemisinin-based combination therapies are recommended as first line treatments for Plasmodium falciparum malaria in most areas of the world. The article by Shahinas et al. (1) describes a patient who had P. falciparum malaria after returning from Nigeria. Her isolate had an elevated 50% inhibitory concentration to artemisinin derivatives. She had obtained artesunate in Nigeria and took it weekly for malaria prophylaxis, which might have contributed to the relative resistance found.

Figure

Figure. Bottle of artemisinin, available over-the-counter as an herbal supplement.

In 2009, one artemisinin-based combination therapy (artemether/lumefantrine) became available for use in the United States. However, it is not widely appreciated that artemisinin is actually available in the United States as an herbal supplement for over-the-counter purchase (2). It is marketed for general health maintenance and for treatment of parasitic infections and cancers (Figure), although as with other supplements it is not intended to diagnose, treat, cure, or prevent any disease. As in the patient described by Shahinas et al., widespread use of artemisinin or its derivatives as monotherapies could potentially lead to progressively increasing resistance in P. falciparum malaria (3). Studies in western Cambodia, where artemisinin monotherapy has been available for many years, have revealed in vivo artesunate resistance, with markedly decreased parasite clearance times (3). Progressive spread of artemisinin resistance could have disastrous consequences for the global control of malaria. Thus, minimally regulated use of potent compounds in dietary supplements has the potential for major public health implications.

Suggested Citation for this Article
Rakita RM. Widespread availability of artemisinin monotherapy in the United States [letter]. Emerg Infect Dis [serial on the Internet]. 2011 May [date cited]. http://www.cdc.gov/EID/content/17/5/954.htm

DOI: 10.3201/eid1705.101532

Comments to the Authors
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To the Editor: We read with interest the report by Wiechmann et al. that, in the investigation of late medieval plague, partial sequencing of the Yersinia pestis pPCP1 plasmid yielded the observation of a 3-T homopolymeric tract which differed from the 5-T homopolymeric tract of the Orientalis Y. pestis CO92 type strain (1). This observation was unexpected because previous data from multispacer sequence typing and glp D gene sequencing yielded only the Orientalis biotype in cases of ancient plague (2).

BLAST analysis (http://blast.ncbi.nlm.nih.gov/blast.cgi) indicated that the 5-T homopolymeric tract has been found only once in the Y. pestis CO92 strain (4) and in none of 22 modern and 11 ancient sequences (Table). This 5-T homopolymeric tract is therefore CO92 strain specific and not a marker for the Orientalis biotype. This pPCP1 plasmid sequence, located into a noncoding region of the 3′ extremity of the plasmid, is characterized by several homopolymeric tracts of poly (A) and poly (T), including the 1 herein investigated. Instability of the T-stretches has been reported in bacterial genomes (5) as being hot spots for mutations (5).

Therefore, in our assessment, the data reported for the late medieval Bavaria burial (1) do not support that deaths of persons buried in this site resulted from a non-Orientalis plague. Typing modern or ancient Y. pestis strains should not rely on poly (A) and poly (T) homopolymeric tracts sequencing.

AbstractOBJECTIVES: To determine the effect of colony-stimulating factor (CSF) on incidence of febrile neutropenia, infection, and survival in older people with non-Hodgkin's lymphoma (NHL) treated with chemotherapy.

DESIGN: Retrospective cohort study.

SETTING: The Surveillance, Epidemiology, and End Results-Medicare database.

PARTICIPANTS: Thirteen thousand two hundred twenty-three people diagnosed with NHL at age 65 and older (mean age 74.9, range 65-102) in 1992 to 2002 who received chemotherapy within 12 months of diagnosis.

MEASUREMENTS: Primary prophylaxis was defined as CSF administered at the start of chemotherapy before febrile neutropenia or infection; secondary prophylaxis was defined as CSF use after febrile neutropenia or infection.

RESULTS: Participants with five to nine administrations of primary prophylactic CSF had a 42% lower risk of febrile neutropenia (odds ratio (OR)=0.58, 95% confidence interval (CI)=0.41-0.83), and participants with 10 or more administrations had a 48% lower risk (OR=0.52, 95% CI=0.36-0.76) after adjusting for age, stage, histology, and comorbidity. Results did not differ significantly after adjusting for propensity score of receiving CSF. There was no significant association between primary prophylactic CSF and overall survival, but secondary prophylactic CSF was significantly associated with better survival. Four to 10 administrations of secondary prophylactic CSF was associated with 9% lower mortality risk (hazard ratio (HR)=0.91, 95% CI=0.84-0.99), 11 to 23 administrations was associated with 23% lower mortality risk (HR=0.77, 95% CI=0.71-0.84) and 24 or more administrations was associated with 13% lower mortality risk (HR=0.87, 95% CI+0.79-0.95) than in participants not receiving CSF after neutropenia or infection.

CONCLUSION: Primary prophylactic CSF was observed to be effective in reducing the incidence of neutropenia and infection. These findings substantiate the clinical guidelines for recommending prophylactic CSF in older people with NHL receiving chemotherapy.

Based on data from 1,032 U.S. hospitals, the Hospital Survey on Patient Safety Culture: 2011 User Comparative Database Report provides initial results that hospitals can use to compare their patient safety culture to other U.S. hospitals. In addition, the 2011 report presents results showing change over time for 512 hospitals that submitted data more than once. The report consists of a narrative description of the findings and four appendixes, presenting data by hospital characteristics and respondent characteristics for the database hospitals overall and separately for the 512 trending hospitals.

The Agency for Healthcare Research and Quality (AHRQ) released the Hospital Survey on Patient Safety Culture [Surveys on Patient Safety Culture], a tool to help hospitals evaluate how well they had established a culture of safety in their institutions, in 2004. A database was also needed so hospitals and units in hospitals could determine how well they were doing in establishing a culture of safety in comparison to other similar hospitals or hospital units.

The Hospital Survey on Patient Safety Culture: 2011 User Comparative Database Report meets that need. Based on data provided voluntarily by 1,032 U.S. hospitals, the Report provides results that hospitals can use as one basis for comparison in their efforts to establish, improve, and maintain a culture of patient safety in their institutions.

The main report presents statistics (averages, standard deviations, minimum and maximum scores and percentiles) on the patient safety culture areas or composites assessed in the survey as well as the survey items.

Appendixes A and B present breakouts of the data by hospital characteristics (bed size, teaching status, ownership and control, region) and respondent characteristics (hospital work area/unit, staff position, interaction with patients). Appendixes C and D show trends over time for the 512 hospitals that administered the survey and submitted data more than once. The average percent positive scores are shown for the composites and items, broken down by hospital characteristics (bed size, teaching status, ownership and control) and respondent characteristics (hospital work area/unit, staff position, interaction with patients).

The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

No investigators have any affiliations or financial involvement (e.g., employment, consultancies, honoraria, stock options, expert testimony, grants or patents received or pending, or royalties) that conflict with material presented in this report.

This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without specific permission of copyright holders.

AbstractBACKGROUND: optimal utilization of therapies effective at preventing arrhythmic death but not nonarrhythmic death, for example, the implantable cardioverter-defibrillator (ICD), is challenging in patients with concomitant heart failure (HF) and chronic kidney disease (CKD), given the association of both conditions with competing risks of death.

OBJECTIVES: we examined the risk of arrhythmic and nonarrhythmic mortality in patients with different severities of HF and CKD.

METHODS: using individual patient data from the SOLVD, we categorized HF by New York Heart Association class and CKD severity by estimated glomerular filtration rate. Cox models with HF and CKD stages as time-dependent covariates were used to calculate hazard ratios for arrhythmic and nonarrhythmic death adjusted for age, gender, and enalapril allocation.

RESULTS: among 6,378 patients without an ICD (age 60 ± 10, left ventricular ejection fraction 27 ± 6, male 86%), there were 421 arrhythmic and 1188 nonarrhythmic deaths over a median follow-up of 34 months. Worse HF or CKD stages were associated with increased risk of both arrhythmic and nonarrhythmic death. The increase in the risk of nonarrhythmic death in the worst HF stage was disproportionately higher than that of arrhythmic death, and this disproportionate effect was more exaggerated in the presence of more advanced CKD.

CONCLUSION: while advanced CKD and HF stages are associated with increased risk of arrhythmic and nonarrhythmic death, benefits of ICDs in patients with more advanced disease may be limited by the preponderance of nonarrhythmic death.

Objectives: To catalog what is known about the safety of interventions containing Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and/or Bacillus strains used as probiotic agents in research to reduce the risk of, prevent, or treat disease.

Data Sources: We searched 12 electronic databases, references of included studies, and pertinent reviews for studies addressing the safety of probiotics from database inception to August 2010 without language restriction.

Review Methods: We identified intervention studies on probiotics that reported the presence or absence of adverse health outcomes in human participants, without restriction by study design, participant type, or clinical field. We investigated the quantity, quality, and nature of adverse events.

Results: The search identified 11,977 publications, of which 622 studies were included in the review. In 235 studies, only nonspecific safety statements were made ("well tolerated"); the remaining 387 studies reported the presence or absence of specific adverse events. Interventions and adverse events were poorly documented.

A number of case studies described fungemia and some bacteremia potentially associated with administered probiotic organisms. Controlled trials did not monitor routinely for such infections and primarily reported on gastrointestinal adverse events. Based on reported adverse events, randomized controlled trials (RCTs) showed no statistically significantly increased relative risk (RR) of the overall number of experienced adverse events (RR 1.00; 95% confidence interval [CI]: 0.93, 1.07, p=0.999); gastrointestinal; infections; or other adverse events, including serious adverse events (RR 1.06; 95% CI: 0.97, 1.16; p=0.201), associated with short-term probiotic use compared to control group participants; long-term effects are largely unknown. Existing studies primarily examined Lactobacillus alone or in combination with other genera, often Bifidobacterium.

Few studies directly compared the safety among different intervention or participant characteristics. Indirect comparisons indicated that effects of delivery vehicles (e.g., yogurt, dairy) should be investigated further. Case studies suggested that participants with compromised health are most likely to experience adverse events associated with probiotics. However, RCTs in medium-risk and critically ill participants did not report a statistically significantly increased risk of adverse events compared to control group participants.

Conclusions: There is a lack of assessment and systematic reporting of adverse events in probiotic intervention studies, and interventions are poorly documented. The available evidence in RCTs does not indicate an increased risk; however, rare adverse events are difficult to assess, and despite the substantial number of publications, the current literature is not well equipped to answer questions on the safety of probiotic interventions with confidence.

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Safety of Probiotics Used to Reduce Risk and Prevent or Treat Disease

Author affiliations: State Key Laboratory of Pathogen and Biosecurity, Beijing, People's Republic of China; and Institute of Microbiology and Epidemiology, Beijing

Suggested citation for this article

To the Editor: Anaplasma phagocytophilum, an emerging human pathogen of public health importance, is transmitted to humans most commonly by tick bites (1). The agent has been detected in various species of Ixodes ticks around the world (2) and in Dermacentor silvarum ticks in northeastern People's Republic of China (3), where 3 A. phagocytophilum strains were isolated from wild and domestic animals (4). In the Asiatic region of Russia adjacent to China, A. phagocytophilum was identified in Ixodes persulcatus ticks, and A. bovis in Haemaphysalis concinna ticks (5). Human granulocytic anaplasmosis was reported in the southern area of the Russian Far East that borders China (6). The objectives of this study were to investigate the prevalence of A. phagocytophilum in ticks collected from the China–Russia border and to characterize the agent by molecular biology techniques.

During May–June 2009, host-seeking ticks were collected by flagging vegetation of grassland or woodland along the China–Russia border. Attached ticks were collected from sheep and goats in Hunchun, and from dogs in Suifenhe (Table). All ticks were identified by morphologic features to the species level and the developmental stage by 2 entomologists (Y. Sun and R.-M. Xu). DNA was extracted from tick samples by using Tissue DNA Extract kit (Tiangen Biotechnique Inc., Beijing, China), following the instructions of the manufacturer. Nested PCR was performed to amplify partial citrate synthase gene (gltA) of A. phagocytophilum as previously described (7). To avoid possible contamination, DNA extraction, the reagent setup, amplification, and agarose gel electrophoresis were performed in separate rooms, and negative control samples (distilled water) were included in each amplification.

A. phagocytophilum was detected in 83 of 2,429 adult ticks, with an overall prevalence of 3.42% (Table). The infection rates in the 14 survey sites ranged from 0 to 5.96%, and were significantly different (χ2 = 24.43, df = 13; p = 0.027). Except for H. japonica, ticks from 4 species, including H. concinna, H. longicornis, I. persulcatus, and D. silvarum were found to be naturally infected. The difference in infection rates among tick species was statistically significant (χ2 = 13.03, df = 4; p = 0.011). Of 367 attached H. longicornis ticks obtained from domestic animals in Hunchun and Suifenhe, 12 (3.27%) were infected with A. phagocytophilum (Table). Nymphal ticks were only collected from vegetation in Hunchun, and 30 pools (10 in each pool) of 1,190 H. concinna nymphs were positive with an estimated minimum prevalence of 2.52%.

Abstract
Venezuelan equine encephalomyelitis (VEE) epizoodemics were reported at 6–10-year intervals in northern South America beginning in the 1920s. In 1937, epizootic VEE virus was isolated from infected horse brain and shown as distinct from the North American equine encephalomyelitis viruses. Subsequently, epizootic and sylvatic strains were isolated in distinct ecosystems; isolates were characterized serologically as epizootic subtype I, variants A/B and C; or sylvatic (enzootic) subtype I, variants D, E, and F, and subtypes II, III, and IV. In 1969, variant I-A/B virus was transported from a major outbreak in northern South America to the borders of El Salvador, Guatemala, and Honduras. This musical poem describes the history and ecology of VEE viruses and the epidemiology of an unprecedented 1969 movement of VEE viruses from South America to equids and humans in Central America from Costa Rica to Guatemala and Belize and in Mexico and the United States that continued until 1972.

Abstract
Tick-borne encephalitis virus (TBEV) is an emerging pathogen in Europe and Asia. We investigated TBEV in Kyrgyzstan by collecting small mammals and ticks from diverse localities and analyzing them for evidence of TBEV infection. We found TBEV circulating in Kyrgyzstan much farther south and at higher altitudes than previously reported.

Tick-borne encephalitis virus (TBEV) is a flavivirus in the family Flaviviridae. The TBEV positive-sense RNA genome is translated as a polyprotein and subsequently cleaved into 3 structural and 7 nonstructural (NS) proteins (1). TBEV has 3 subtypes— European, Siberian, and Far-Eastern—each of which has its own ecology, clinical presentation, and geographic distribution (2). The vectors are Ixodes ricinus ticks for the European subtype and I. persulcatus ticks for the other 2 subtypes. TBEV circulates through a complex cycle involving small mammals, ticks, and large mammals (3); it can also be transmitted through consumption of unpasteurized milk and milk products (4).

Our unpublished data and that of others suggest that TBEV circulates in Kazakhstan. However, we have found no reports (in English) since 1978 of TBEV infection in the neighboring Kyrgyz Republic (Kyrgyzstan). Kyrgyzstan has extensive alpine and subalpine habitats (94% of Kyrgyzstan is >1,000 m above sea level) (5); the Tien Shan mountain range dominates and physiographically links Kyrgyzstan to the Himalayas and western People's Republic of China. We conducted fieldwork in Kyrgyzstan during June–July 2007 and July–August 2009 to establish a baseline of risk for zoonotic diseases, including TBEV.